1. New Psychiatric Medications
Knowledge is Power
Gregory T. Bogart, Pharm.D., BCPP
Clinical Psychiatric Pharmacist
University of Maryland, School of Pharmacy
Springfield Hospital Center
Sykesville, MD
Jennifer Miller, Pharm.D., BCPP
Wilkes-Barre VAMC
Wilkes-Barre, PA

2. Objectives
Discuss clinical indications of new and emerging psychiatric medications
Compare and contrast the role of new medications with existing medications
Implement strategies to learn about new psychiatric medications

3. Antipsychotics

4. Oral Antipsychotics 1st Generation 2nd Generation
Thorazine® (chlorpromazine)
Clozaril® (clozapine)
Haldol® (haloperidol)
Risperdal® (risperidone)
Prolixin® (fluphenazine)
Geodon® (ziprasidone)
Stelazine® (trifluperazine)
Seroquel® (quetiapine)
Trilafon® (perphenazine)
Zyprexa® (olanzapine)
Navane® (thiothixene)
Abilify® (aripipirazole)
Loxitane® (loxapine)
Invega® (paliperidone)
Mellaril® (thioridazine)
Fanapt® (Iloperidone)
Saphris® (Asenapine)
Latuda® (Lurasidone)

5. Long Acting Injectable Antipsychotics
1st Generation
2nd Generation
Haloperidol decanoate
Risperdal Consta®
Fluphenazine decanoate
Invega Sustenna®
Zyprexa Relprevv®
Abilify Maintena®

6. New Oral Antipsychotics

7. Iloperidone FDA approved in 2009
Indicated for the treatment of schizophrenia in adults
Mechanism of action – primarily dopamine (D2) antagonism with some serotonin (5HT2) antagonism
Fanapt® [package insert]. East Hanover, NJ;
Novartis Pharmaceuticals Corporation; Revised April, 2014.

8. Iloperidone - Efficacy
6-week trial with placebo and risperidone showed superiority over placebo and comparable efficacy of risperidone at 6 weeks
4-week trial with placebo and ziprasidone found superiority over placebo and similar efficacy to ziprasidone at 4 weeks
Fanapt® [package insert]. East Hanover, NJ;
Novartis Pharmaceuticals Corporation; Revised April, 2014.

9. Iloperidone – Possible Side Effects
Metabolic changes – weight gain, ↑cholesterol
Not as significant as other 2nd gen drugs
Extrapyramidal symptoms (EPS)
QTc prolongation
Orthostasis, low blood pressure, and dizziness
Rarer side effects – priapism, seizure, agranulocytosis

10. Iloperidone - Dosing Starting dose 1 mg twice daily
Target dosage range 6-12 mg twice daily
Increase by no more than 2 mg twice daily every day until target range
Slow titration due to increased risk of low blood pressure, dizziness, and falls
Maximum dose of 12 mg twice daily
Fanapt® [package insert]. East Hanover, NJ;
Novartis Pharmaceuticals Corporation; Revised April, 2014.

11. Iloperidone – Role in therapy
New second generation antipsychotic choice
Lower risk for EPS and weight gain than other options
Higher risk of orthostasis, dizziness, and falls especially during the initial titration phase
Slow titration phase and twice daily dosing may be difficult for some patients to work with

12. Asenapine FDA approved in 2009 Indications
Treatment of schizophrenia in adults
Acute treatment, either as monotherapy or adjunctive, or manic or mixed episodes of bipolar I disorder in adults
Mechanism of action thought to be a combination of dopamine D2 and serotonin 5HT2 receptor blockade
Saphris® [package insert]. Whitehouse Station, NJ;
Merck & Co., Inc.; Revised March, 2013.

13. Asenapine – Efficacy in Schizophrenia
Short term studies
A 6-week trial comparing asenapine to placebo showed superior efficacy asenapine at 6 weeks
A 6-week trial comparing asenapine to placebo and haloperidol showed asenapine to be superior to placebo, but not haloperidol. It also showed no difference between 5 mg twice daily and 10 mg twice daily dosing
A 6-weeks trial comparing asenapine to placebo olanzapine showed that asenapine and placebo failed to separate and that olanzapine was superior to both
Saphris® [package insert]. Whitehouse Station, NJ;
Merck & Co., Inc.; Revised March, 2013.

14. Asenapine – Efficacy in Bipolar I Disorder
Monotherapy
Two 3-week trials of asenapine and placebo showed that asenapine was superior to placebo for controlling acute mania
Adjunctive
A 12-week trial of asenapine or placebo added to lithium or valproic acid showed asenapine was superior to placebo at reducing manic symptoms at 3 weeks
Saphris® [package insert]. Whitehouse Station, NJ;
Merck & Co., Inc.; Revised March, 2013.

15. Asenapine – Possible Side Effects
Metabolic changes and weight gain
Not as significant as other 2nd gen drugs
EPS – higher rates of akathisia
QTc prolongation
Sedation or somnolence
Headache
Rarer side effects – agranulocytosis, seizures, and orthostasis
Saphris® [package insert]. Whitehouse Station, NJ;
Merck & Co., Inc.; Revised March, 2013.

16. Asenapine - Dosing Asenapine is supplied as sublingual tablets
Do not swallow tablets
Dissolve under the tongue
No food or drink for 10 minutes after dose
Indication
Starting Dose
Dosage Range
Maximum
Schizophrenia
5 mg twice daily
5-10 mg twice daily
10 mg twice daily
Acute Bipolar I
Saphris® [package insert]. Whitehouse Station, NJ;
Merck & Co., Inc.; Revised March, 2013.

17. Asenapine – Role in Therapy
Can be utilized in both schizophrenia and bipolar disorder
Unique sublingual administration
Relatively small metabolic side effects
Higher rates of sedation and akathisia than other agents

18. Lurasidone FDA approved in 2010 Indications
Treatment of schizophrenia in adults
Treatment of depressive episodes in bipolar disorder in adults as both monotherapy and adjunctive therapy
Mechanism of action thought to be a combination of dopamine D2 and serotonin 5HT2 receptor blockade
Latuda® [package insert]. Marlborough, MA;
Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

19. Lurasidone – Efficacy in Schizophrenia
Five total trials, all 6 weeks long
Two trials of fixed dose lurasidone vs. placebo showed superior efficacy of lurasidone
One trial of 40 mg, 80 mg, and 120 mg lurasidone vs. placebo showed that only the 80 mg dose was superior to placebo
One trial of lurasidone, olanzapine and placebo showed that both lurasidone and olanzapine were superior to placebo
One trial of lurasidone, quetiapine ER, and placebo showed both lurasidone and quetiapine ER were superior to placebo
Latuda® [package insert]. Marlborough, MA;
Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

20. Lurasidone – Efficacy in Bipolar Depression
As monotherapy
A 6-week trial vs placebo for symptom reduction in bipolar depression showed that both doses of lurasidone studied were superior to placebo at 6 weeks
As an adjunct
A 6-week trial of patients who were still symptomatic on lithium or valproic acid were given placebo or lurasidone. At 6 weeks, there was a superior symptom reduction in the lurasidone group vs. the placebo group
Latuda® [package insert]. Marlborough, MA;
Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

21. Lurasidone – Possible Side Effects
Metabolic changes and weight gain
Possibly the most weight and metabolic neutral
EPS – akathisia more common than others
QTc prolongation
Sedation or somnolence
Nausea and vomiting
Rarer side effects – agranulocytosis, seizures, and orthostasis
Latuda® [package insert]. Marlborough, MA;
Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

22. Lurasidone - Dosing
For schizophrenia, starting dose is 40 mg/day with a range of mg/day
For bipolar depression, starting dose is 20 mg/day with a range of mg/day
All doses should be taken with a meal of at least 350 calories to improve absorption
Dosing is recommended in the evening due to the possibility of sedation and somnolence
Latuda® [package insert]. Marlborough, MA;
Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

23. Lurasidone – Role in Therapy
Can be utilized in schizophrenia and bipolar depression
Has a very favorable long-term metabolic profile
Once daily dosing is most patient friendly
Appears to be the most rigorously studied of the newer agents

24. Long Acting Injections (LAIs)

25. Rationale LAIs are options to improve compliance
Less frequent administration than oral agents
Doses converted from stable oral regimens
Guaranteed drug level in the body post-injection
Improved clinician contact

26. Available Options 1st Generation 2nd Generation Haloperidol decanoate
Risperdal Consta®
Fluphenazine decanoate
Invega Sustenna®
Zyprexa Relprevv®
Abilify Maintena®

27. Zyprexa Relprevv® FDA approved in 2009
Long acting intramuscular injection of olanzapine intended for gluteal injection only
Indicated for the treatment of schizophrenia
Designed to be initiated after a stable regimen of olanzapine is established
Zyprexa Relprevv® [package insert]. Indianapolis, IN;
Eli Lilly and Company; Revised July, 2011.

28. Zyprexa Relprevv® - Dosing
Oral dose of olanzapine
Dose of Zyprexa Relprevv® for the first 8 weeks
Maintenance dose of Zyprexa Relprevv®after 8 weeks
10 mg/day
210 mg every 2 weeks or
405 mg every 4 weeks
150 mg every 2 weeks or
300 mg every 4 weeks
15 mg/day
300 mg every 2 weeks
20 mg/day
Note: No oral medication overlap is required
Zyprexa Relprevv® [package insert]. Indianapolis, IN;
Eli Lilly and Company; Revised July, 2011.

29. Adverse Events Adverse events are similar to oral olanzapine
Metabolic syndrome and weight gain
Sedation
Orthostasis and dizziness
Also has Post-Injection Delirium/Sedation Syndrome (PDSS) risk
Zyprexa Relprevv® [package insert]. Indianapolis, IN;
Eli Lilly and Company; Revised July, 2011.

30. PDSS Signs and symptoms associated with olanzapine overdose
Sedation and/or delirium possibly leading to coma
Dizziness, confusion, disorientation, slurred speech, weakness, difficulty walking
Occurred in <0.1% of all injections, 2% of all patients treated in 46 months
Most patients recovered with supportive care within 72 hours
Lead to the creation of a REMS program
Zyprexa Relprevv® [package insert]. Indianapolis, IN;
Eli Lilly and Company; Revised July, 2011.

31. Zyprexa Relprevv® REMS
Prescriber, patient, facility, and pharmacy must all register
Medication cannot be dispensed directly to patient
Medication must be administered in a registered facility with access to emergency response services
Patients must be observed by a healthcare worker for at least 3 hours after injection for signs of PDSS
Patients may not leave the facility by themselves
Patients should not drive the remainder of the day
Zyprexa Relprevv® [package insert]. Indianapolis, IN;
Eli Lilly and Company; Revised July, 2011.

32. Abilify Maintena® FDA approved in 2013
Long acting intramuscular injection of aripiprazole intended for gluteal injection only
Indicated for the treatment of schizophrenia
Designed to be initiated after a stable regimen of aripiprazole is established
Abilify Maintena® [package insert]. Tokyo, Japan;
Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

33. Abilify Maintena® Dosing
Recommended starting dose in 400 mg monthly
Continuation of oral aripiprazole mg/day is necessary for 14 days after initial injection
Maintenance dose is also 400 mg monthly
Dose reduction to 300 mg can be used if 400 mg dose is intolerable
Abilify Maintena® [package insert]. Tokyo, Japan;
Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

34. Adverse Events Very similar to oral aripiprazole
Slight metabolic changes
Some EPS – mostly akathisia
Anxiety
Headache
Orthostasis
Abilify Maintena® [package insert]. Tokyo, Japan;
Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

35. Antidepressants

36. Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Celexa® (citalopram)
Cymbalta® (duloxetine)
Lexapro® (escitalopram)
Effexor® (venlafaxine)
Prozac® (fluoxetine)
Pristiq® (desvenlafaxine)
Paxil® (paroxetine)
Savella® (milnacipran)
Luvox® (fluvoxamine)
Fetzima® (levomilnacipran)
Zoloft® (sertraline)
Brintellix® (vortioxetine)
Viibryd® (vilazodone)
Also paxil cr, luvox cr and effexor xr

37. Antidepressants Tricyclic Antidepressants Atypical Antidepressants
Monoamine Oxidase Inhibitors (MAOIs)
Elavil® (amitriptyline)
Wellbutrin® (bupropion)
Nardil® (phenelzine)
Anafranil® (clomipramine)
Remeron® (mirtazapine)
Parnate® (tranylcypromine)
Tofranil® (imipramine)
Serzone® (nefazodone)
Eldepryl® (selegiline)
Pamelor® (nortriptyline)
Desyrel® (trazodone)
Marplan® (isocarboxazid)*
Norpramin® (desipramine)
Sinequan® (doxepin)
Vivactil® (protriptyline)
Doxepin has greatest AH

38. New Oral ANTIDEPRESSANTS

39. Viibryd® (Vilazodone)
Year Approved
2011
Indication
Major Depressive Disorder
Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised December, 2012.
Image from

40. Viibryd® (Vilazodone)
Mechanism of Action
Selective Serotonin Reuptake Inhibitor (SSRI)
Activity at serotonin receptor
Effectiveness
Decreased depressive symptoms in 8 week trials better than placebo
Partial 5HT-1A agonist
Decreased depressive symptoms in two 8 week RCT trials of outpatients
Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised December, 2012.

41. Viibryd® (Vilazodone)
Safety
Contraindications
Use with MAOI
Warnings
Serotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuation
Suicidality – In children, teenagers & young adults <= 24 y/o. Monitored for change in mood, thoughts, behaviors, actions or feelings and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during initial few months and dose changes. Daily observation by family & caregivers.
SS – GI upset, agitation, hallucinations, delirium, and coma, autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea
Seizure – not studied
Hyponatremia & bleed – no cases but with other SSRIs – headache, weakness, confusion
Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised December, 2012.

42. Viibryd® (Vilazodone)
Safety
Drug interactions
Adverse Effects
Nausea, diarrhea, dizziness, sleep disturbance, sexual dysfunction
DI - 3A4 substrate, NSAIDs, Serotonergic meds/MAOIs
Transient vs chronic
Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised December, 2012.

43. Viibryd® (Vilazodone)
Considerations for Use
Take with food
Dose titration
No dose adjustment for age
Pregnancy, nursing, or children
Medication Role
No clear advantage over SSRIs for depression
W/ food – or decrease [] by 50%
Titration - 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then an increase to 40 mg once daily
No human data in preg, lactation or children
Viibryd ® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised December, 2012.

44. Fetzima® (Levomilnacipran)
Year Approved
2013
Indication
Major Depressive Disorder
More active enantiomer of milnaciprin (approved in 2009 for fibromyalgia)
More selective for NE - Tx norepinephrine deficiency symptoms - decreased concentration, lassitude, mental and physical slowing, and decreased self-care.3,4 Some authors claim that individual patients could experience improvement in their social and occupational functioning in addition to improvement in the core symptoms of depression.5
Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised July, 2013.
Image from

45. Fetzima® (Levomilnacipran)
Mechanism of Action
Serotonin Norepinephrine Reuptake Inhibitor (SNRI)
Effectiveness
Decreased depressive symptoms in 8 week trials better than placebo
Decreased depressive symptoms in three 8 week RCT trials of outpatients (40-120mg all doses superior)
Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised July, 2013.

46. Fetzima® (Levomilnacipran)
Safety
Contraindications
Allergic reaction, uncontrolled narrow-angle glaucoma, use with MAOI
Warnings
Serotonin syndrome, suicidality, seizure, mania, bleed, low sodium, sudden discontinuation
Warnings not based on evidence directly from levomilnacipran
Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised July, 2013.

47. Fetzima® (Levomilnacipran)
Safety
Warnings (cont.)
High blood pressure & heart rate, narrow-angle glaucoma, urinary hesitation or retention
Drug interactions
Adverse Effects
Nausea, vomiting, constipation, sweating, increased blood pressure & heart rate, sexual dysfunction
These warnings are based off data with levomilnacipran
Strong 3A4 inhibitors like ketoconazole; avoid doses > 80mg/day; other medications which can increase BP & HR
No dose adjustment needed for 3A4 inducers
(Other: serotonergic/MAOIs, drugs increasing BP & HR, drugs affecting homeostasis – NSAIDs)
Alcohol accelerated drug release from ER capsules
Urinary hestitation & erectile dysfunction were dose related
Although BP avg increase was only 3mmHg and HR was 7 bpm…trials excluded patients with significant CVD
Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised July, 2013.

48. Fetzima® (Levomilnacipran)
Considerations for Use
Adjust dose for kidney impairment
No dose adjustment for age
Pregnancy, nursing, children
Medication Role
No clear advantage over SNRIs for depression
No established effectiveness for fibromyalgia/ pain
Pregnancy – decreased birth weight and possibly mortality in rats at supratherapeutic doses.
Nursing – present in rat milk
Children – no data
Once daily dosing; ER tablet – do not split, etc
Both in-vitro and in-vivo studies found that levomilnacipran exhibited more potency for NE reuptake inhibition than for 5-HT reuptake inhibition at the lowest effective dosage (10 mg/kg). However as the dosage was increased (20 mg/kg and 40 mg/kg), it was equally potent at NE and 5-HT reuptake inhibition. This is in contrast to venlafaxine, which demonstrates a similar, but opposite, effect in terms of potentiation at the 5-HT and NE reuptake pumps.2
NNT 6; NNT VNL was 8
Fetzima® [package insert]. St. Louis, MO; Forest Laboratories, Inc.;
Revised July, 2013.

49. Brintellix® (Vortioxetine)
Year Approved
2013
Indication
Major Depressive Disorder
Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals
America, Inc.; Revised July, 2014.
Image from us.brintellix.com

50. Brintellix® (Vortioxetine)
Mechanism of Action
SSRI
Activity at various serotonin receptors
Effectiveness
Decreased depressive symptoms in 6-8 week trials & longer time to recurrent depression in 64 week trial better than placebo
5HT3, 1D, 7 antagonism, 1A agonism, 1B partial agonist
5mg not effective in 6-8 week trials; took 2 weeks for initial effect and about 4 weeks for full effect
Short term studies with outpts and were RCTs; Longterm study was open label with inpts and outpts
Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals
America, Inc.; Revised July, 2014.

51. Brintellix® (Vortioxetine)
Safety
Contraindications
Allergic reaction, use with MAOI
Warnings
Serotonin syndrome, suicidality, mania, bleed, low sodium
Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals
America, Inc.; Revised July, 2014.

52. Brintellix® (Vortioxetine)
Safety
Drug interactions
Adverse Effects
Nausea, vomiting, constipation, dizziness, sexual dysfunction
The maximum recommended dose of BRINTELLIX is 10 mg/day in known CYP2D6 poor
metabolizers. Reduce the dose of BRINTELLIX by one half when patients are receiving a
CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly.
Consider increasing the dose of BRINTELLIX when a strong CYP inducer (e.g., rifampin,
carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum
recommended dose should not exceed three times the original dose.
Nausea was dose related and resolved after ~ 2 weeks
No changes in weight or vital signs observed in pre-marketing trials
Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals
America, Inc.; Revised July, 2014.

53. Brintellix® (Vortioxetine)
Considerations for Use
Avoid in severe liver impairment
No dose adjustment for age
Pregnancy, nursing, children
Medication Role
No clear advantage over SSRIs for depression
-10 mg administered orally once daily without regard to
meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses
demonstrated better treatment effects in trials conducted in the United States. The efficacy and
safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose
decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses
-Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients
experienced transient adverse reactions such as headache and muscle tension following
abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse
reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full
discontinuation of BRINTELLIX 15 mg/day or 20 mg/day
Developmental delays in rats; no adequate human trials; present in rat milk; no studies in peds; no dose adj needed for geri (like other 2 ad’s)
No dose adj for geri, race, ethnicity, (like other ad’s) up to severe renal dys, but unknown with severe hepatic disease
Brintellix® [package insert]. Deerfield, IL; Takeda Pharmaceuticals
America, Inc.; Revised July, 2014.

54. Miscellaneous Medications

55. Miscellaneous Medications
Methyl – 2012
Zolpid
Images taken from

56. Learning Strategies

57. Resources NAMI.org FDA.gov Drugs.com MedlinePlus Narsad.org
Medication fact sheets
FDA.gov
Drugs.com
MedlinePlus
Narsad.org
Seek info on the internet; talk with health care providers!
NAMI – inform yourself at bottom left – about medications at bottom left
FDA- a lot of links, but search function works well
The site features FDA Consumer Update articles, videos, and slideshows.  Site users can get valuable access to information about new drug approvals, use a drug interaction checker to check the compatibility of using two drugs at the same time, identify drugs from their tablet and capsule markings, ask questions to other site users, join support groups, and much more. Site users can also subscribe to the Drugs.com electronic newsletter and also sign up to receive alerts from FDA's MedWatch.    
MedlinePlus also offers a wide range of information about prescription drugs and dietary supplements.  Additionally, this site provides information about many medical conditions and health issues treated with prescription medications.  The site also provides a medical encyclopedia, a medical dictionary, an aid to find local health-related resources, and current health news and press announcements.  The site can be used on over 40 languages. 
Narsad.org – “ask an expert”; blurbs about research and can search by mental illness
National Alliance for Research on Schizophrenia and Depression – the Brain and Behavior Research Foundation